miacalcic training 2004 platform syr april 03

MIACALCIC® Nasal Spray

Training course

2004

Introduction In 1969, Novartis developed an injectable concentration of calcitonin-salmon for

use in the treatment of osteoporosis.

This new drug became available in the United States in 1984

1995 the FDA had approved a new, more convenient form of calcitonin salmon: MIACALCIC® Nasal Spray.

This formulation is indicated for the treatment of post-menopausal osteoporosis in women at least 5 years postmenopause who refuse or cannot tolerate estrogens or for whom estrogens are not an option.

As a result of these innovations, and with the recent additions of other treatment options, osteoporosis is no longer seen as merely an unfortunate consequence of aging; it is now a treatable medical disease.

Introduction Because of our aging population, osteoporosis becomes more

prevalent each year.

In fact, 1 of every 2 women over 50 years of age will sustain an osteoporosis-related fracture in her lifetime.

As osteoporotic patients increase in number, so will the demand for easy, effective treatment.

It is important to have a knowledgeable sales force for MIACALCIC Nasal Spray.

Prevalence of Osteoporosis The prevalence of a disease is the total number of cases in existence in

a given population at a certain time.

The prevalence of osteoporosis has risen dramatically over the last decade and will continue to rise as the population over 60 years of age increases.

In the United States today, an estimated 44 million people, 80% of whom are women, have or are at risk of developing osteoporosis.

Approximately 10 million Americans have osteoporosis, while 34 million have low bone mass, which indicates an increased risk for the disease.

The majority of cases go undiagnosed, leading to significant undertreatment of the disease.

Incidence of Osteoporotic Fractures The incidence of a disease or condition is the rate at which it occurs, that is, the

number of new cases occurring during a given period of time (eg, the number of hip fractures per year).

The incidence of a disease provides a basis for statements of probability of risk of illness.

Because the majority of people with osteoporosis are asymptomatic until a fracture occurs, it is difficult to directly measure the precise incidence of osteoporosis.

When bone mass reaches the “fracture threshold,” fracture risk increases significantly.

Rates of certain types of bone fracture provide an indirect measure of the incidence of osteoporosis, since fracture is the main clinical consequence of osteoporosis.

Illustration of decreases in bone mass with age >10 years.

Osteoporosis Market

According to the National Osteoporosis Foundation, osteoporosis leads to more than 1.5 million fractures in the United States each year, including: 700,000 vertebral fractures 300,000 hip fractures 200,000 wrist fractures 300,000 other fractures

Osteoporosis Market

Emphasis is often placed on hip fractures due to the significant mortality associated with their occurrence (5% to 20% of patients die within the first year)

It should be noted that vertebral compression fractures are more than twice as common as hip fractures and are associated with significant morbidity.

Once vertebrae are deformed by fracture, they never return to their normal shape; such deformities can accumulate over time, leading to kyphosis, disability, chronic back pain, and height loss.

Because more women are living longer, it follows that the incidence of osteoporosis will also increase dramatically.

Illustration of the relationship between osteoporosis-associated fractures and age.

Osteoporosis risk statistics

1 of every 2 women over 50 years of age will have an osteoporosis-related fracture in her lifetime

40% of all women will have at least 1 spinal fracture by the time they reach 80 years of age

A woman’s risk of hip fracture is equal to her combined risk of breast, uterine, and ovarian cancer

Socioeconomic Costs of Osteoporosis

The socioeconomic costs of osteoporosis are extensive.

Social costs include pain, emotional stress, deformity, immobility and death.

It is estimated that osteoporotic fractures result in 40,000 to 50,000 deaths in the United States each year.

Monetary costs of osteoporosis and osteoporosis-related fractures, which include the cost of hospitalization and nursing home care, were estimated to be $17 billion in 2001 ($47 million per day) in the United States alone.

Hip fractures have the greatest social and economic impact of all osteoporotic fractures, producing substantial disability and mortality.

This type of fracture often requires lengthy hospitalization and, at times, surgery.

More than half of osteoporosis-related hospitalizations involve hip fractures.

Socioeconomic Costs of Osteoporosis

Moreover, hip fractures may lead to a number of serious and potentially life-threatening complications, such as pneumonia and lung blood clots (pulmonary emboli) from immobilization.

The total cost of treatment per hip fracture is estimated to exceed $30,000.

In addition, pain and disability associated with hip and other osteoporosis-related fractures may severely impair performance of activities of daily living.

Osteoporotic patients may also experience fatigue, depression, sleep disorders, reduced self-esteem, and anxieties such as fear of falling.

Many of those who survive hip fractures suffer permanent disability and dependency. They may isolate themselves from family and friends, which further reduces their quality of life.

The costs of osteoporosis

Clearly, postmenopausal osteoporosis is an extremely prevalent disease, impacting millions of lives with potentially serious consequences. Although currently less than 15% of postmenopausal women receive medication for osteoporosis, this number is expected to grow rapidly in the coming years, due to, in large part, to the marketing and selling efforts of MLACALCIC Nasal Spray and its competitors.

Pain Extensive hospitalization

Decreased quality of life Rehabilitation

Loss of productivity Home healthcare

Disability

Emotional stress

Medical Background Medical Background KnowledgeKnowledge

Functions of Bone Bones have many important and diverse functions

Structurally, bones are like the building’s framework:

1- they support the body 2- protect its vital organs 3- provide the necessary muscle attachment sites and leverage for movement.

But bones function also manufacture and store red blood cells, platelets, and some types of white blood cells.

In addition, they store and release calcium, phosphorus, sodium, and magnesium ions.

Functions of Bone The storage and release of calcium ions influence many vital bodily

functions, including the structure of bone:

1. Calcium is critical to maintaining the strength, hardness, and rigidity of bone.

2. Important in several electrophysiological reactions, which are basically electrical reactions associated with bodily functions. These include the mechanisms that control cardiovascular and neuromuscular function.

3. Calcium works in conjunction with many enzymes and hormones to execute important biochemical reactions in the body, such as those that control the ability of substances to pass through cell membranes.

Functions of Bone

1. Supports the body

2. Protects the vital organs

3. Provides muscle attachment leverage for movement

4. Stores and manufactures red blood, cells, platelets, and some types of white blood cells

5. Stores and releases calcium, phosphorus, sodium, and magnesium ions

General Structure of Bone

The skeleton has 2 divisions:

1. Appendicular skeleton2. Axial skeleton

All bones of the body are composed of 2 major types of mineralized tissue:

1. Cortical bone2. Trabecular bone

General Structure of Bone

The appendicular skeleton includes:1. limbs2. shoulders3. pelvis

The axial skeleton is composed of:1. skull2. spine3. sternum4. ribs

Figure 1-2 shows the location of these 2 types of bone tissue in a long bone (femur) and a vertebra. As you can see, cortical bone, or compact bone, generally comprises the outside portion of each bone. This is referred to as the cortical envelope. Although it has some vascularization (that is, it contains blood vessels), cortical bone appears uniformly dense and hard. Approximately 75% to 80% of the skeleton is cortical bone. A relatively higher amount is found in the appendicular skeleton.

Trabecular bone, also called spongy or cancellous bone

Highly vascularized (contains many blood vessels) and spongy in appearance.

It comprises the inner portions of the vertebrae and the ends of the long bones.

A relatively high amount of it is found in the axial skeleton.

Postmenopausal osteoporosis primarily affects trabecular bone.

Trabecular bone is much less dense than cortical bone and has a higher remodeling rate

So osteoporosis affects trabecular bone to a greater degree than cortical bone.

Trabecular BoneTrabecular Bone

Although bone has a mineral-like texture, it is living tissue.

Like all tissue, bone contains networks of blood vessels and nerve fibers.

Blood vessels supply nutrients and other important components to the bone.

The long bone (femur) it is divided into 2 regions: the epiphysis (ends) and diaphysis (shaft).

Within the long bone is the medullary cavity, which contains marrow.

Trabecular bone also contains marrow.


There are 2 types of marrow: red and yellow.

Red marrow manufactures red blood cells and platelets.

As an individual ages, red marrow becomes partially transformed into yellow marrow, which is inactive.

The periosteum is a strong fibrous membrane that covers the entire bone except at the joint surfaces.

These are covered by articular cartilage


Long Bone-Femur

Chemistry of Bone Bone is composed of both organic and inorganic components that give it

remarkable structural properties.

To function in its supportive and protective role, bone must have both compressional and tensile strength.

Compressional strength allows the bone to be hard and firm enough to protect the body and provide leverage for movement.

Tensile strength gives the bone flexibility so that it will not shatter upon impact. In this way, bones are like bridges.

The bridge contains a groundwork of steel beams, which give it tensile strength, and is reinforced with concrete, which gives it compressional strength.

Chemistry of Bone In bone, protein fibers called the organic matrix, or osteoid, function like

the bridge’s steel beams.

This organic matrix provides tensile strength.

Ninety-five percent of the organic matrix is composed of collagen, a fibrous protein that provides bone with elasticity.

Structures made of fibrous proteins, such as tendons and ligaments, are well known for having exceptional tensile strength—they can resist considerable pull before breaking.

The remainder of the organic matrix is made up of a homogeneous organic medium called ground substance.

Bone Mineral Density

Bone mineral density (BMD) is the term used to express the amount of bone tissue either within the entire skeleton or within a portion of the skeleton.

It is the major, although not the only, determinant of resistance to fracture.


An individual’s BMD is influenced by a variety of factors: Age Calcium intake Sex Structural errors and defects Genetic makeup Environmental factors, such as physical activity, alcohol and

caffeine intake, and smoking

The 2 most important factors influencing bone mass are age and sex.


As a child grows, BMD increases until it reaches a peak mass at around the age of 30 to 35 years.

Peak BMD tends to be greater in males than females.

BMD stays at its peak value for a few years until age-related bone loss begins.

Although BMD declines over the years in both sexes, it is more rapid in women.


Accelerated bone loss occurs when women stop producing estrogen at menopause (at approximately 50 years of age).

BMD may reach such a low level that fractures may occur during ordinary movement.

This level is referred to as the fracture threshold.

Females generally cross the fracture threshold before males because of their lower peak BMD and accelerated bone loss after menopause.

Bone Modeling and Remodeling

Bone modeling is the process by which the skeleton grows to adult size and shape.

As each bone in the skeleton grows, its size and shape are adjusted to respond to mechanical stresses.

Bone modeling is determined primarily by genetic influences, but can also be affected by other factors, such as general nutrition, the amount of calcium ingested, and the level of physical activity.

Even after reaching its adult size, a bone continuously changes in response to changing stresses and demands.

Not only is the bone material constantly breaking down and being reabsorbed into the blood, it is also continuously being re-formed.


Taken together, these continuous processes of bone resorption and bone formation are called bone remodeling or bone turnover.

Remodeling is required for growth, repair, and replacement of worn-out bone.

Overall, about 8% of bone tissue is remodeled per year.

This rate varies with age; bone remodeling occurs more rapidly in the young than in the elderly.

Also, remodeling is more rapid in trabecular bone than in cortical bone—as high as 20% to 30% per year.


Bone remodeling is influenced by the demands placed on the bone by the individual.

It can either strengthen or weaken bone.

For example, bone remodeling will strengthen the bones in a karate expert’s hands due to the continued demands exerted on them.

In contrast, the unused bones of an invalid will become weaker.

The Process of Bone Remodeling

Two types of cells are primarily responsible for bone remodeling: osteoblasts and osteoclasts

Osteoblasts form bone and mineralize the bone matrix, primarily with calcium and phosphorous

Osteoclasts break down and resorb bone, releasing calcium and phosphorus into the blood.


During quiescence, lining cells cover the bone surface.

In the subsequent resorption phase these cells are converted into multinucleate osteoclasts, which break down bone by engulfing and digesting whole fragments of organic matrix and inorganic bone salt.

Osteoclasts are also thought to secrete osteoblast-activating factor, which assists in the generation of osteoblasts


Next, in the reversal phase, cells of uncertain origin smooth over the resorbed surface and deposit the cement line, which separates the new bone from the surrounding older bone.

The formation of new bone—osteogenesis-—is divided into early and late phases.

In the early phase, osteoblasts deposit a thick layer of bone matrix (osteoid) on the cement line.

In late formation, the osteoblasts nearly finish producing osteoid, and a layer of new mineralized bone forms between the cement line and the osteoid seam.


The cycle of bone remodeling is complete when the quiescent surface is restored.

The cavity has now been completely refilled to form a new bone structural unit (BSU).

In general, old bone must be destroyed by osteoclasts before new bone can be built by osteoblasts.

Thus, the 2 processes of resorption and new bone formation are normally coupled.

Calcium’s Role in the Body

Calcium is a mineral, represented by the chemical symbol Ca++.

Calcium accounts for about 2% of total body weight of adults.

99% of the body’s calcium is stored in the bones and teeth, with the remaining 1% distributed throughout the tissues and the blood.

Calcium Homeostasis

Strict maintenance of the blood calcium level within a narrow range is critical to human life.

Deviations from this range can result in serious and sometimes fatal consequences, such as malfunction of the heart muscle.

Achieving the correct blood calcium levels is part of homeostasis, the maintenance of constant conditions within the body’s internal environment.

Calcium Homeostasis

Homeostasis often involves interactions among different systems of the body.

Many of these interactions are regulated by hormones.

Blood calcium levels are regulated at 3 sites in the body:1. The skeleton (site of calcium storage)2. The gastrointestinal (GI) tract (site of calcium absorption)3. The kidney (site of calcium excretion)

Calcium Homeostasis

The mechanism by which blood calcium levels are regulated in the skeleton is bone remodeling.

Bone formation moves calcium from the blood into the bone, decreasing serum calcium levels

Bone resorption moves calcium from the bone to the blood, increasing blood calcium levels.

Calcium Homeostasis

A state of calcium balance exists when 2 things happen.

First, bone formation equals bone resorption.

Second, calcium absorption through the GI tract equals calcium excretion through the kidneys.

Calcium Homeostasis

Calcium homeostasis is regulated primarily by 2 hormones: parathyroid hormone and calcitonin, with the aid of vitamin D.

Each of these hormones affects bone remodeling, calcium absorption, and/or calcium excretion.

Which hormones are activated depends on whether blood calcium levels are low or high.

Low Blood Calcium Levels

In response to low blood calcium concentration, parathyroid hormone (P7711) is secreted by the epithelial cells of the parathyroid glands.

PTH has the following 3 effects, each of which increases the blood calcium concentration: Increases bone resorption in the skeleton Increases calcium absorption in the GI tract Decreases calcium excretion in the kidneys

Low Blood Calcium Levels

Vitamin D is both obtained from the diet (eg, from fortified milk) and manufactured by the skin upon exposure to sunlight.

The liver and kidneys metabolize vitamin D into an active form, known as 1 ,25-dihydroxyvitamin D3 or calcitriol, which facilitates GI absorption of calcium.

High Blood Calcium Levels

In response to high serum calcium concentration, calcitonin is secreted by specialized cells, called parafollicular or C cells, in the thyroid gland.

Calcitonin decreases blood calcium levels by: Decreasing bone resorption in the skeleton Increasing calcium excretion in the kidneys


Calcitonin slows bone resorption by inhibiting osteoclastic activity.

Calcitonin may also increase osteoblastic activity.

Over the long-term, calcitonin ultimately prevents osteoclast formation.

Calcitonin, therefore, helps to maintain calcium reserves in bone and to inhibit calcium release into the blood.

In addition, calcitonin further decreases blood calcium levels by increasing renal excretion of calcium.

The effects of calcitonin on bone resorption and calcium excretion are, for the most part, the opposite of those of PTH.


In addition to PTH, calcitonin, and vitamin D, other hormones may affect blood calcium concentrations.

The hormone estrogen has a strong influence on calcium metabolism.

Research has shown that estrogen exerts a bone-protective effect.

Estrogen may also improve calcium absorption and inhibit calcium excretion.


Other hormones that affect bone metabolism, and therefore calcium balance, include thyroid hormones, growth hormones, and androgens.

Non-hormonal factors may also affect bone metabolism:1. decreased dietary calcium and phosphorus intake,2. high levels of dietary protein,3. increasing age 4. immobilization5. certain drugs6. stress

Osteoporosis-Definition

Osteoporosis, as defined by the World Health Organization (WHO) in 2000, is a disorder in which BMD is -2.5 standard deviations (SD) below the average BMD of young healthy adult women.

A patient with 1 or more low-trauma fractures is considered to have osteoporosis regardless of the BMD value.

The FDA has a less stringent standard, defining the condition as - 2.0 SD below the average BMD.

For the purpose of this document and MIACALCIC® Nasal Spray, we will use the definition of the WHO.


It should be noted that in a statement issued following the National Institutes of Health (NIH) Consensus Conference held in March 2001:

Bone strength was defined as comprising 2 characteristics: bone density and bone quality.

Bone density is expressed in terms of grams of mineral per area or volume.

When diagnosing osteoporosis, a patient’s BMD is compared with the BMD of young, healthy women.


Bone quality, on the other hand, refers to the architecture, turnover, damage accumulation, and mineralization of the bone.

It is possible that in some patients osteoporosis is not only the result of bone loss but may be the result of accumulated microfractures, sub-optimal bone development during childhood or adolescence, or other factors affecting bone quality.

However, BMD accounts for about 70% of bone strength.

Clinically, the pronounced loss in BMD associated with osteoporosis presents as an increased risk of fracture—bones may fracture under stress simply because bone loss has become so great.

Osteoporotic fractures, particularly in the early stages of osteoporosis, may be very small (microfractures) and may cause little or no pain.


Osteopenia is a less severe decrease in BMD, which is greater than 1 SD but less than 2.5 SD below the average BMD of healthy, young adults.

Clinically, osteopenia often goes undetected because bone loss has not progressed to the degree where fractures occur.

In terms of the fracture threshold, patients with osteoporosis have crossed the threshold, and patients with osteopenia will cross the threshold at some point in the future unless something prevents further bone loss.


The loss of bone mass characteristic of osteoporosis is due to impaired bone remodeling, which results in an increase in bone resorption, a decrease in bone formation, or both.

Osteoporotic bone has the same chemical composition as healthy bone but is less dense.

This feature distinguishes osteoporosis from other bone diseases, such as Paget’s disease, in which the bone is distinctly abnormal.

The effects of osteoporosis on cortical and trabecular bone.

Figure Shows the effects of osteoporosis on cortical and trabecular bone.Figure Shows the effects of osteoporosis on cortical and trabecular bone.

Types of Osteoporosis

The 2 major divisions of osteoporosis are: Primary osteoporosis Secondary osteoporosis

Primary osteoporosis is more common

80% to 90% of all cases of osteoporosis are primary.

Primary osteoporosis occurs mostly in older people, and much more frequently in females.


Primary osteoporosis can be subdivided into 2 major classifications: Postmenopausal (or type I) osteoporosis Senile (or type II) osteoporosis

Secondary osteoporosis occurs as a consequence of an endocrine disorder (or some other chronic disease) or from the use of a drug that causes bone loss.

Endocrinologic disorders that cause secondary osteoporosis include glucocorticoid excess, parathyroid and thyroid hormone excess, hypogonadism, and diabetes.


Drugs that affect bone metabolism, such as corticosteroids and thyroid hormone, may lead to osteoporosis.

New research suggests that prolonged steroid use affects the life cycle of bone cells.

High doses of steroids not only reduce the number of bone-forming cells but also cause them to die prematurely.

Secondary osteoporosis can occur in both sexes, and in children as well as adults.

Characteristics of Primary (Postmenopausal and Senile) and Secondary steoporosis

Postmenopausal Senile Secondary

Sex Female Male/Female Male/Female

Reasons Menopause, estrogen

deficiency, genetic

Predisposition, dietary and lifestyle factors

Old age, age- related Disorders

chronic disorder, chronic use of certain drugs

(ie. Corticosteroids)

Age of onset

10 years after menopause (often

begins 55-60; can begin earlier)

Usually after age 75

Any age

Primary Osteoporosis

Postrnenopausal osteoporosis is related to the estrogen deficiency that occurs after menopause, resulting in an increase in bone loss after menopause and, therefore, occurs only in females.

It is suggested that estrogen directly inhibits bone resorption, and when the female body stops producing it at menopause, it leads to postmenopausal bone loss.

In addition, recent studies have demonstrated a decline in circulating calcitonin levels following menopause, leading to an increase in osteoclast activity.

Fractures resulting from postmenopausal osteoporosis typically begin to be noticed in women 10 years after menopause, and they primarily affect trabecular bone.


Women with postmenopausal osteoporosis have trabecular bone loss 3 times greater than women of the same age group without osteoporosis.

Postmenopausal osteoporosis causes fractures mainly in the vertebrae, which called vertebral fractures.

There are also non-vertebral fractures that include the femoral neck and forearm (distal radius).


The femoral neck is the upper part of the femur, close to the hip joint.

The term “hip fracture” is actually a misnomer, since it is the femoral neck, not the pelvis, that is commonly fractured.

A fracture of the forearm or distal radius is referred to as a Colles’fracture.

In older men, bone formation declines with age while bone resorption continues at its previous rate.


In older women, bone formation declines with age while bone resorption actually accelerates after menopause.

Although senile osteoporosis occurs in both sexes, it is more common in women than men (2 to 1 ratio).

The reduction of calcium absorption from the GI tract that occurs with age also contributes to senile osteoporosis.

Older patients, particularly those in long-term care (LTC) facilities, may have reduced levels of vitamin D due to changes in vitamin D metabolism and less sun exposure.

Senile osteoporosis affects cortical and trabecular bone equally. It commonly results in fractures of the hip (femoral neck) and the vertebrae.

““hip fracture”hip fracture”

Colles’fractureColles’fracture

Clinical Signs and Symptoms The early stages of osteoporosis, in general, are difficult to diagnose.

Overt signs of osteoporosis generally do not occur until the disease is at an advanced stage.

The first indication of osteoporosis is a spontaneous fracture with resulting pain.

Virtually all of the clinical consequences of osteoporosis result from the fracture or collapse of bones and the resulting pain and restriction of mobility.

In more advanced cases of osteoporosis, fractures may occur almost spontaneously upon rolling over in bed.

More commonly, vertebral fractures occur while getting up or bending over, whereas limb and hip fractures typically occur during falls.

Clinical Signs and Symptoms

The most common areas of vertebral fractures are in the thoracic or lumbar regions of the spine.

Vertebral fractures due to osteoporosis are often referred to as compression fractures, in which the vertebrae compress or collapse.

Compression fractures are categorized as either wedge fractures or crush fractures.

In a wedge fracture, the anterior portion of the vertebral collapses.

In a crush fracture, the entire vertebra collapses.

Wedge fractures are very common in osteoporotic patients.

Crush fractures are less common and generally cause more pain and disability.

Clinical Signs and Symptoms As the osteoporotic individual ages, continued compression

fractures of thoracic vertebrae cause the spine to curve

Curvature of the spine characteristic of postmenopausal osteoporosis is called kyphosis or, “dowager’s hump.”

Curvature of the spine can result in the loss of several inches of height.

In extreme cases, kyphosis can interfere with breathing by reducing the size of the thoracic and abdominal cavities.

Clinical Signs and Symptoms Patients with osteoporosis generally experience 2 types of back

pain.

Some patients may suddenly experience sharp and severe pain, which is coincident with a new vertebral compression fracture and aggravated by motion.

The other, more common pain is a dull ache of long duration.

This type of pain is usually a result of repeated vertebral compressions and fractures, causing the distortions in normal spinal anatomy described above.

Clinical Signs and Symptoms One consequence of osteoporosis may eventually be fatal:

immobilization due to fractures.

Confining an elderly patient to bed may compromise respiratory and cardiovascular function and contribute to the development of life-threatening pneumonia and pulmonary emboli.

In addition, immobilization often results in loss of independence, reduced quality of life, and mental depression.

Once bedridden, an elderly patient may never regain the ability to walk.

Clinical Signs and Symptoms

Many patients with hip fractures never fully recovering

Requiring expensive nursing care for the rest of their lives.

Predisposing Factors for Osteoporosis

Many factors, including diet, lifestyle, medical history, and genetics, greatly influence the risk of developing osteoporosis.

Increasing age and female sex are the most important risk factors for osteoporosis.

As previously noted, osteoporosis is most common in women over the age of 55.


The 2 main reasons for this risk are that women generally attain a lower maximum bone mass than men and lose bone mass more rapidly after menopause.

Premature menopause, including that induced by oophorectomy, the surgical removal of the ovaries, may further increase the risk.


Physical characteristics such as thin build and low body weight may also increase the risk of osteoporosis.

Women with a thin build begin adult life with less bone mass. In addition, women with low body weight have less body fat.

This increases osteoporotic risk because fat cells convert androgens into estrogen. In addition, ovaries produce estrogen.

Estrogen exerts a bone-protective effect. Fewer fat cells means less estrogen production and decreased bone protection.


Nutritional factors also play’ an important role in the pathogenesis of osteoporosis.

The most important nutritional factor is calcium intake, particularly during times of high calcium demand, such as childhood and pregnancy.

Calcium is critical to maintaining bone strength, and an inadequate calcium intake may increase the risk of osteoporosis.

For reasons that remain largely undefined at present, heavy alcohol, cigarette, and caffeine use all increase the risk of osteoporosis.

Long-term use of certain medications, such as corticosteroids and thyroid hormones, also increase osteoporotic risk.

Risk Factors for the Development of Osteoporosis in summery

Advanced age, Female gender Estrogen deficiency

Prolonged premenopausal amenorrhea (>1 year) Early menopause (<age 45) or bilateral ovariectomy Natural menopause

Caucasian (especially Northern European) or Asian* Small frame (slenderness) Low body weight (<127 lbs)/muscle mass ratio Family history of osteoporosis Nutritional factors

Inadequate calcium intake (lifelong) Excessive caffeine intake Inadequate intake of vitamin D

Excessive alcohol consumption Current cigarette smoking Chronic corticosteroid medication Inactivity, prolonged immobilization Certain diseases

Hyperthyroidism Hyperparathyroidism Kidney disease

Paget’s Disease

Paget’s disease is a chronic bone disorder with accelerated and irregular bone turnover primarily due to overactive osteoclasts and evidenced by extremely high serum concentrations of the enzyme alkaline phosphatase, often reaching twice the normal level.

There is also secondary osteoblast hyperactivity, in which the body apparently attempts to compensate for the marked resorption.

The resulting increase in bone turnover leads to irregularly structured bone tissue that is larger than normal and mechanically weak.

Patients with Paget’s disease are susceptible to fracture.

Paget’s Disease

The cause of Paget’s disease is not yet fully understood.

It appears to be the result of both genetic predisposition and an environmental factor, most likely a virus.

The skeleton is never affected as a whole; the spine, femur, skull, sternum, and pelvis are the most common locations for Paget’s lesions. Often just 1 section of a single bone may be affected.

Paget’s disease is usually asymptomatic, but bone pain occasionally develops.

This is typically dull and aching and present both during activity and at rest. Osteoarthritis and its accompanying pain are usually present, making diagnosis difficult.

Paget’s Disease

Two biochemical indicators that measure bone turnover, alkaline phosphatase blood levels and hydroxyproline urine levels, can be useful in the diagnosis of Paget’s disease.

Complications of Paget’s disease may include fracture and neurologic damage (if the bones of the vertebrae and skull are involved).

Calcitonin-salmon injectable and the bisphosphonates, alendronate and risedronate, are indicated for the treatment of Paget’s disease in men and women.

Hypercalcemia

Hyperadcemia, as the name suggests, is an elevated blood calcium level.

Hypercalcemia may be an acute or chronic condition.

Acute hypercalcemia is characterized by:1. rapid onset2. Severe symptoms3. Short duration

Chronic hypercalcemia is generally characterized by a more gradual onset, moderate symptoms, and a longer duration.

Hypercalcemia Both conditions can ultimately be fatal.

Hypercalcemia is a symptom of bone diseases.

It is often caused by increased bone resorption, which results in the release of calcium into the bloodstream.

Bone metastaces are a common cause of bone cell destruction and resorption, leading to hypercalcemia.

Other causes of hypercalcemia include abnormal parathyroid function and tumor production of hormones that resorb bone, often found in cases of metastasized cancer.

Diagnosis of Osteoporosis

Bone diseases are diagnosed and monitored using a variety of methods

Ranging from simple x-rays and laboratory tests to sophisticated techniques for measuring bone mineral density.

The Diagnosis of Osteoporosis

Clinical presentationCharacteristics and location of painLoss of height and/or mobilityMedical history

Measurement of bone Noninvasive imaging techniques Bone biopsy

For postmenopausal osteoporosis, the most common clinical signs and symptoms are pain, reduced mobility, and loss of height due to vertebral fracture.

Sharp, severe back pain that is especially aggravated by motion is coincident with a new vertebral fracture.

The pain is dull and aching and of long duration.

This chronic pain is the result of repeated compression fractures of the vertebrae, which cause distortions in normal spinal anatomy (kyphosis).


Sometimes the patient’s medical history can suggest the possibility of osteoporosis.

The long-term use of certain medications, such as corticosteroids, can result in osteoporosis.

For diagnosing osteoporosis, measurement of BMD is standard.

Methods for measuring bone mass include imaging techniques.



Osteoporosis is characterized by loss of bone mass or BMD.

Measuring BMD may help in diagnosing osteoporosis and predicting the risk of fracture.

In addition, it can be valuable in monitoring a patient’s response to treatment.

Over the past 20 years, a number of noninvasive procedures have been developed to measure bone mass.

Conventional X-Ray Techniques

Conventional x-ray’ may detect the presence of a fracture, which may lead to a diagnosis of osteoporosis.

30% to 40% of bone must be lost before it can be detected by x-rays.

This technique is not very useful for detecting postmenopausal osteoporosis because it is not sufficiently sensitive and measures only gross bone deformities.

Dual X-Ray Absorptiometry

Dual x-ray absorptiometry (DXA), or dual-energy x-ray absorptiometry (DEXA), determines bone mass by measuring the decrease in the strength of radiation that passes through tissue at the site being evaluated.

DXA is the preferred method of bone densitometry because it allows precise measurement of BMD at both the hip and spine as well as the whole body.

Single x-ray absorptiometry (SXA), which uses technology similar to DXA, is available to measure peripheral sites of the skeleton with relatively constant soft tissue thickness and composition, such as the heel or forearm.


SXA has only 1 x-ray beam, whereas DXA has 2 beams, each with different energy levels that provide the means to correct for absorption due to soft tissue.

Peripheral sites can also be assessed by DXA.

Portable peripheral DXA (pDXA) devices have become available that are particularly useful for office evaluation, and are relatively’ inexpensive and more convenient.


The Peripheral Instantaneous X-Ray Imager (PIXI) measures bone density at the heel.

Measurement of BMD at most sites, including the hip, spine, and peripheral sites, is a good predictor of fracture risk.

Hip bone density is the measurement considered the most useful predictor of hip fracture risk, particularly in older women.


Results from bone densitometers are expressed in standard units of mg/cm2 and given in absolute or relative terms (T-scores and Z-scores).

The Z-score is the number of standard deviations from the age-matched average value of healthy women.

For example, if a 55-year-old woman were being tested, her Z-score would be compared to that of a healthy 55-year-old woman.

The T-score is the number of standard deviations from the value at peak mineral density of young healthy 25- to 35-year-old Caucasian women.


Unlike T-scores, Z-scores always indicate whether or not the BMD is lower than it should be for a patient’s age and sex.

Nevertheless, T-scores are used more often so it’s important to know that a T-score lower than -2.5 on a standard DXA scan shows that the patient has osteoporosis and pharmacologic intervention may be considered to prevent fractures.

A T-score between -1 and -2.5 shows that a patient is osteopenic and pharmacologic therapy may be considered depending on the patient’s overall risk profile.

Quantitative Ultrasound

Qyantitative utrasound (QUS) measures BMD.

The principle underlying this technique is that the speed at which ultrasound (high-frequency) sound waves move through bone is determined by the density and inherent material quality (i.e, ability to resist fracture) of bone.

The higher the bone density, the higher the speed of ultrasound.

Bones with high US velocity are high in strength and resist fracture when force is applied.

In contrast, bones with low US velocity deform more with force and are less able to resist fracture.

Quantitative Ultrasound

Most of the QUS devices are used to measure trabecular bone at the heel.

Measurements of BMD have been found to correlate well with bone structure and strength.

QUS is free from ionizing radiation, low in cost, portable, fast (3 to 5 minutes to complete), and easy to use.

One disadvantage of QUS in assessing heel bone density is its inconvenience, since it requires water or gel as an acoustic coupling medium.

Bone Biopsy

Bone biopsy is the removal of bone tissue from the body for examination.

Bone biopsy’ is considered to be the most accurate method of distinguishing between osteoporosis and other metabolic bone disorders.

The technique allows for assessment of the degree of mineralization, the quantity’ and structure of trabecular bone, the number of active bone cells, and the rates of bone formation and resorption.

Bone Biopsy

Bone biopsy is rarely used because it is expensive and painful, and because of the risk of complications (eg, infection) arising from invasive procedures.

Bone biopsy is most often used in clinical trials evaluating it osteoporosis therapies to determine whether the bone that is generated is of normal quality.

Biochemical Markers

Evidence of bone formation and resorption, or bone turnover, can be detected in serum or urine by the presence of a number of biochemical markers

They consist of enzymes from bone cells, by’products of bone matrix synthesis, or breakdown products of bone.

A marker is a substance that is useful for monitoring a particular process, such as bone metabolism, and that is easily obtainable or detectable through laboratory tests.

By measuring the levels of these biochemical markers of both bone formation and resorption, rates of bone turnover can be determined.

Biochemical Markers

Bone turnover assessment is primarily used to monitor response to therapy for osteoporosis.

Results of tests to measure biochemical markers demonstrate response to therapy more quickly (ie, within 6 months) than densitometry.

It may help to motivate patients who are asymptomatic.

While preliminary data indicate that biochemical markers may predict fracture risk independent of bone mass assessment, larger and more prolonged studies are needed to confirm these findings.

These results are limited because they do not indicate the amount of bone that is lost or quality of bone formed.

Pytidinium Cross-Links

The urinary pytidinium cross-links, pytidinoline and deoxypyridinoline, are bone resorption markers.

Pytidinoline is found in type II collagen of cartilage, but the majority excreted in the urine originates in the bone.

Deoxypytridinoline is only found in type I collagen of bone and, therefore, provides a highly’ specific measure of bone resorption.

Type I Collagen Telopeptides

Collagen is composed of chains of polypeptide proteins, which are degraded during bone resorption.

During this process, the ends of the polypeptides, called telopeptides, are split-off and released into the bloodstream.

There are 2 types of these fragments, cross-linked N-telopeptide (NTx) and C-telopeptide (CTx), which can be used as indicators of bone resorption.

Hydroxyproline

Hydroxyproline is an amino acid that is found primarily in collagen,

It is not specific for type I collagen of bone.

It is a product of bone degradation and therefore of osteoclast activity.

Changes in blood and urinary hydroxyproline levels can be used as biochemical indicators of collagen breakdown and, therefore, of bone resorption.

Hydroxyproline

Certain conditions associated with increased bone resorption (eg, Paget’s disease) are associated with high urinary excretion of hydroxyproline.

This biochemical test is not as useful in the diagnosis of osteoporosis, because patients with osteoporosis usually have normal urinary hydroxyproline levels.

Alkaline Phosphatase

Measuring serum levels of alkaline phosphatase can reflect disease states of liver or bone.

In bone, alkaline phosp hatczse is a by-product of bone synthesis (osteoblast activity) and is the usual marker for osteoblastic bone formation.

Serum alkaline phosphatase levels can reflect overall bone turnover

Elevated levels suggest increased metabolic activity (ie, rapid turnover) in the bone.

Alkaline Phosphatase

Alkaline phosphatase is useful in the diagnosis and evaluation of Paget’s disease, in which bone turnover is highly accelerated.

Use of total alkaline phosphatase as a marker of bone formation is limited because it is not bone-specific but rather is found also in the liver, kidneys, and the intestines.

However, assays that measure bone-specific alkaline phosphatase have been developed, which improves its potential for use in measuring bone turnover and projecting fracture risk.

Osteocalcin

Osteocalcin is a non-collagen protein that is produced by the osteoblast during bone formation.

It is released into the circulation during bone resorption.

Unlike alkaline phosphatase, serum osteocalcin reflects bone turnover rather than solely bone formation.

Increases in both gradual age-related and accelerated postmenopausal bone turnover can be detected through measurement of serum osteocalcin.

Osteocalcin

Levels of serum osteocalcin have been useful in detecting secondary causes of bone loss. Radioimmunoassays and enzyme-linked immunoassays are used to measure serum osteocalcin.

Who Should Be Screened?

The broadest definition of a candidate for bone mass measurement, as suggested by the International Society for Clinical Densitometry, is any patient, regardless of age or gender, if the final result of the test will influence a clinical decision.

Typically, however, the indications for bone mass measurement are more specific.


Guidelines from the American Association of Clinical Endocrinologists (AACE) and those from Medicare recommend testing patients falling into 1 of the following categories:

Postmenopausal, or otherwise estrogen-deficient, women concerned about osteoporosis and willing to begin available treatments

Women with x-ray results that suggest osteopenia, osteoporosis, or vertebral abnormalities

Women on long-term glucocorticoid therapy Postmenopausal women with asymptomatic primary

hyperparathyroidism Patients undergoing treatment for osteoporosis


With the increasing usage and success of therapeutic options available for osteoporosis, bone mass screening is an important tool in the measurement of patients’ response to therapy.

In such cases, it is recommended that patients have a bone screening every 1 to 2 years.

However, for patients with very rapid bone loss, such as those receiving long-term treatment with glucocorticoids, bone screenings should be performed every 6 months.


Currently, Medicare covers diagnostic screening for patients if they fall into at least 1 out of 5 diagnostic categories. These categories include individuals who:

Are estrogen-deficient and at clinical risk of osteoporosis Are receiving long-term glucocorticoid (steroid) therapy Have vertebral abnormalities Have primary hyperparathyroidism Are being monitored to assess the response to, or efficacy of, an

approved osteoporosis drug therapy

Current options range from non-pharmacologic intervention only to the use of a number of FDA-approved medications.

In light of the growing market of medications available for osteoporosis, an understanding of the advantages and disadvantages of each is essential to achieve optimum clinical outcomes.

Therapy for OsteoporosisTherapy for Osteoporosis

Non-pharmacologic Interventions

There are a number of non-pharmacologic measures to help minimize bone loss and fracture risk:

1. weight-bearing exercise

2. calcium and vitamin D supplementation

3. fall prevention.

4. In the elderly, improvements in muscle strength, coordination, and flexibility may help to prevent falls and, therefore, reduce fracture risk.

Non-pharmacologic Interventions

Diseases and ‘impairments that may predispose a patient to falls such as visual or gait abnormalities should be treated.

Medications with side effects that increase a patient’s risk of falling should be avoided if possible.

Avoidance of risk factors, such as smoking, high alcohol intake, and high caffeine intake, is also recommended to prevent or control osteoporosis.

Pharmacologic Preventive and Therapeutic Modalities

Pharmacologic therapy’ to prevent osteoporosis may include :

1. Estrogens (eg, Premarin®, PremproTM, Wy’eth-Ayerst; Estraderm®, Vivelle®, Novartis)

2. Alendronate (Fosamax®, Merck)3. Risedronate (Actonel®, Procter & Gamble)4. Raloxifene (Evista®, Eli Lilly)

Also, clinical studies are currently’ being conducted to evaluate the use of parathyroid hormone (PTH) as an anabolic therapeutic agent for the treatment and prevention of osteoporosis.


Candidates for prevention therapy include:

1. Those with clinical risk factors for osteoporosis such as Caucasian or Asian descent

2. slender body build3. early estrogen deficiency4. smoking alcohol consumption5. low-calcium diet6. sedentary lifestyle7. family history of osteoporosis.8. results of densitometry indicating low (BMD) stand deviation <2.5

SD below the mean for healthy young women or analysis of biochemical markers suggesting high bone turnover are also risk factors to be considered.


MIACALCIC Nasal Spray, Evista, Fosamax, and Actonel are indicated for the treatment of osteoporosis in postmenopausal women.

Candidates for osteoporosis treatment include patients with very low BMD (>2.5 SD below the premenopausal mean) or with a previous fracture.

Use of Pharmacologic Agents in the Management of Postmenopausal Osteoporosis

*In 2000, the FDA clarified that estrogen is not indicated for the treatment of osteoporosis due to the lack of supporting data. Therefore, estrogen is only approved for the prevention of osteoporosis. Adequate amounts of calcium and vitamin D intake are recommended with all therapies.

Drug Indicated prevention

Indicated for treatment

Calcitonin-salmon nasal spray No Yes

Calcitonin-salmon injection No Yes

Estrogen Yes No*

Alendronate Yes Yes

Risedronate Yes Yes

Raloxifene Yes Yes

Estrogens

The hormone estrogen plays an important role in calcium metabolism and exerts a strong stabilizing effect upon bone mass.

Estrogen replacement therapy (ERT), or hormone replacement therapy (HRT), which is a combination of estrogen and progesterone, is often used to compensate for the drop in estrogen production at menopause.

Estrogen therapy’ is used to manage postmenopausal symptoms (eg, hot flashes), as well as to prevent or delay osteoporosis.

Currently; several estrogens are commercially available.

Estrogens

The exact mechanism by which estrogen affects bone mass is unknown, although it is thought to be through indirect actions on other hormones.

One theory suggests that estrogen stimulates calcitonin secretion, which in turn reduces bone resorption.

Another theory holds that estrogen may counteract the effect of parathyroid hormone (PTH) on bone, thereby decreasing PTH-mediated bone resorption.

Effects on bone mass and fracture risk

ERT, in conjunction with calcium and vitamin D supplements, is effective in both increasing bone mass and preventing osteoporosis.

In a 3-year study; both spinal and hip BMD improved significantly with ERT, with average increases of 5.1% and 2.3%, respectively.

Incidence of hip and wrist fractures was reduced approximately 60% in case-controlled studies in Caucasian women when estrogen was started within a few years of menopause.

Effects on bone mass and fracture risk

To achieve optimum benefit from ERT for the prevention of osteoporosis, it is recommended that women begin therapy within 5 years of menopause in order to prevent excess bone loss from occurring.

They should continue therapy indefinitely because some studies have found that upon discontinuation, bone loss recurs.

Estrogen replacement should be carefully individualized since long-term use has been associated with an increased risk of uterine and breast cancer in predisposed patients.

Safety considerations and adverse effects

ERT is not universally accepted.

Many physicians are reluctant to prescribe estrogens, and many patients are reluctant to take estrogens, for several reasons.

Some evidence suggests that estrogens may only temporarily decrease the rate of bone loss, especially if therapy does not start until many years after menopause.

In addition, the safety and side-effect profile of estrogen therapy is highly complex.


The most serious concern surrounding ERT (unless the woman has had a hysterectomy) is the risk of endometrial cancer, cancer of the interior lining of the uterus.

Women who receive estrogen therapy for up to 5 years have a 6-fold increase in the risk of endometrial cancer, and long-term use raises the risk to 15-fold.


If progesterone (progestin) is used concurrently with estrogen (hormone replacement therapy or I-JRT), the risk of endometrial cancer becomes negligible.

Data from a study conducted by the Women’s Health Initiative (WHI) suggest that other risks may outweigh the benefits of this combination therapy.

In fact, one arm of the planned 8-year study, designed to focus primarily on the prophylactic benefit of HRT (PremproTM) provided in 1 daily tablet containing conjugated equine estrogen (CEE) 0.625 mg and medroxy progesterone acetate (MPA) 2.5 mg on cardiovascular disease, was discontinued in June 2002 after only 5 years because of the increased incidence of invasive breast cancer.


There was also evidence that estrogen/ progesterone therapy increased the risk of coronary heart disease, as well as stroke and pulmonary embolism.

Most of the adverse events were observed in the first 1 to 2 years of the study, except for breast cancer, which showed increased risk after 3 years.

On the other hand, the Will study showed that HRT therapy did decrease the risk of colorectal cancer and hip fractures.

And while the study on women taking combination hormone therapy was discontinued, another arm of the study concentrating on women receiving estrogen alone was not stopped.


The risk of breast cancer in women who receive long-term estrogen therapy alone is still under investigation.

A personal history of breast cancer is still regarded as a specific contraindication for estrogen therapy.

According to most experts, patients must be routinely monitored through frequent breast examinations and annual mammograms.

Significant history of thromboembolic disease is also a contraindication to estrogen.

Other situations in which estrogen should be prescribed with caution include a prior history of migraine headaches or uncontrolled hypertension and/or congestive heart failure.


The most common side effect of ERT is withdrawal bleeding.

It is the shedding of endometrial tissue that occurs when estrogens are used for only part of a monthly cycle.

Many post menopausal women object to this renewed vaginal bleeding.

Other side effects include breast tenderness and weight gain.

Prior to 2000, it was assumed that estrogen was approved for the treatment and prevention of osteoporosis.

Due to a lack of supporting data, the FDA clarified that estrogen is only indicated for the prevention of postmenopausal osteoporosis.

Nevertheless, estrogen is the most widely prescribed medication for osteoporosis prevention.

Administration Estrogen replacement preparations can be administered in several ways.

Tablets, which are absorbed into the systemic circulation and exert widespread effects (including the inhibition of bone loss), are commonly used.

Vaginal creams, applied locally, are used primarily for localized relief of symptoms associated with declining estrogen levels and cannot be used in the management of osteoporosis.

Transdermal patches have systemic effects and are approved for the prevention of postmenopausal osteoporosis.

Daily intake of calcium and vitamin D supplements should be maintained with estrogen replacement

Calcitonin

Calcitonin is a hormone produced from the parafollicular cells (C cells) of the thyroid gland.

Along with parathyroid hormone and vitamin D, calcitonin plays a major role in bone metabolism and calcium homeostasis.

As a therapeutic agent, the main effects of exogenous calcitonin are:1. Inhibition of bone resorption2. Relief of osteoporotic pain (off-label use)3. The most important action of calcitonin is to slow down bone resorption

through the inhibition of osteoclast activity. 4. Calcitonin may also stimulate osteoblastic bone formation to a small

degree.5. Numerous clinical studies have demonstrated the effectiveness of

calcitonin salmon in stopping bone loss and increasing bone mass in postmenopausal women.

Available agent 1. Calcitonin-salmon (MIACALCIC Nasal Spray and Injectable, Novartis)

Bone-disease indications 1. Calcitonin-salmon nasal spray: second-line therapy to estrogen in treatment of osteoporosis in women >5 years postmenopause

2. Injectable calcitonin-salmon: hypercalcemia, Paget’s disease, postmenopausal osteoporosis

Effects 1. Inhibits osteoclast activity

2. May increase osteoblast activity

Use in osteoporosis 1. To stabilize bone mass and increase bone mineral density

Safety 1. Considered safe and well tolerated

2. Most common side effects with nasal spray: rhinitis and other nasal symptoms; occasionally therapy has to be discontinued due to nasal bleeding or ulcerations

3. Most common side effects with injectable: nausea, local inflammatory reactions at the site of injection, and flushing of the face or hands; side effects tend to dissipate in the course of treatment and are dose-related

Mode of administration 1. Nasal spray

2. Subcutaneous injection

Although calcitonin is not indicated to relieve pain, both the subcutaneous injection and nasal spray forms of calcitonin have been shown in small studies to have an analgesic (pain-relieving) effect.

Alleviation of pain in osteoporotic patients leads to increased mobility and overall clinical improvement The mechanisms underlying this effect are not clear, but several theories have emerged.

Calcitonin may’ reduce pain by suppressing prostaglandins (substances that are involved in inflammation and pain).

Calcitonin may also modification the sensitivity of pain receptors or influence the release of beta-endorphins (naturally occurring painkillers).

A final theory suggests that calcitonin modifies the perception of pain through a direct effect on the central nervous system or change in blood flow.

Calcitonin

There are 3 types of calcitonin: salmon, eel, and porcine.

All forms are available in Europe, but only calcitonin-salmon is currently available in the United States.

Calcitonin-salmon is used in conjunction with calcium and vitamin D supplements for the treatment of post-menopausal osteoporosis.

Calcitonin

Effects of bisphosphonates on bone mass and fracture risk

Data from large US and multinational studies demonstrated that alendronate (Fosamax, Merck) significantly increased spinal, hip, and total body bone mass in postmenopausal women with osteoporosis over a period of 3 years.

Results also showed that the proportion of women with new vertebral fractures was reduced by 47%.

Risedronate (Actonel, Procter & Gamble and Aventis Pharmaceuticals as co-marketers) is indicated for the prevention and treatment of postmenopausal osteoporosis.

A large multinational and North American study of women with established osteoporosis showed that risedronate 5 mg daily increases BMD at the spine, nonvertebral, and wrist compared to placebo over a 3-year period of time.

Three-year results also demonstrated a decrease in the risk of new vertebral fractures by 41% to 49%.


The risk of new vertebral fractures was significantly reduced by 65% within the first year of treatment with risedronate compared to placebo.

These data allowed Actonel to position itself at launch as a rapidly acting bisphosphonate.

The risedronate clinical trials included 60% of patients who used nonsteroidal anti-inflammatory drugs (a frequent cause of GI complications) or aspirin regularly and 40% who had ongoing GI diseases such as ulcers, esophagitis, and heartburn.

The results showed that the incidence of GI side effects in risedronate-treated patients was similar to placebo-treated patients.


Therefore, Procter & Gamble was also able to stress that risedronate was well-tolerated even in patients with GI disease.

However, like alendronate, risedronate has the same complex dosing require ments, which may have an impact on patient compliance.

Nevertheless, the risedronate clearly indicates that bisphosphonates may cause upper gaslromtestinal disorders such as dysphasia, esophagal, and esophageal or gastric ulcers.

It also stresses the importance of taking the med ication as instructed to minimize the risk of these adverse events.

Available agents in the United States

Alendronate sodium (Fosamax, Merck)Risedronate (Actonel, Procter and Gamble and Aventis Pharmaceuticals)Pamidronate (Aredia, Novartis)Zoledronic acid (Zometa, Novartis)

Indications Alendronate: prevention and treatment of postmenopausal osteoporosis; treatment of osteoporosis in men; treatment of corticosteroid-induced osteoporosis (CIO); Paget’s diseaseRisedronate: prevention and treatment of osteoporosis, CIO, Paget’s diseasePamidronate: treatment of hypercalcemia, Paget’s disease, osteolytic bone metastases of breast cancer, and osteolytic lesions of multiple myelomaZoledronic acid: treatment of hypercalcemia of malignancy, bone metastases of solid tumors, multiple myeloma

Use in Osteoporosis AlendronateRisedronate

Effects Bisphosphonates: bind to bone salts (calcium phosphate) and decrease bone resorption by inhibiting osteoclasts

Safety Alendronate: abdominal pain is most frequent side effect; precaution about use in patients with ulcers, active upper GI disorders, or renal impairmentRisedronate: same precautions as alendronate; however its side-effect profile has yet to be determined outside of the clinical settingPamidronate: muscular and skeletal pain and feverZoledronic acid to avoid renal impairment, infusion should not exceed 4 mg over 15 minutes; fever, nausea, constipation

Mode of administration Alendronate and risedronate: oral (on an empty stomach)Pamidronate: intravenous administrationZoledronic acid: intravenous administration


Bisphosphonates are poorly absorbed and irritating to the GI system.

GI disturbances and musculoskeletal pain are the most common adverse effects associated with use of oral binsphosphonates.

They have an extended half-life and may remain in the body for longer than 10 years.


Possible negative effects of this prolonged half-life are not yet known.

GI disturbances including abdominal pain, nausea, dyspepsia, constipation, and diarrhea are the most common adverse events reported.

There have been reports of some cases of esophageal erosion and ulcers.

Musculoskeletal (bone, muscle, or joint) pain has also been reported.

Administration

Fosamax and Actonel tablets must be taken on an empty stomach at least 30 minutes before the first food, beverage, medication, or dietary supplements of the day, with at least 6 to 8 ounces of plain water.

In addition, patients must remain upright for at least 30 minutes after taking the drug.

Contraindications include esophageal abnormalities such as stricture that slows down emptying of the esophagus, inability to stand or sit upright for at least 30 minutes, hypersensitivity to any component of the medication, and hypocalcemia.

Because these drugs are eliminated by the kidney, they are not recommended for patients with severe kidney disease (creatinine clearance <35mL/min).

Administration

Fosamax has different dosing requirements for its treatment and prevention indication.

Treatment: Fosamax as a treatment for osteoporosis, the recommended dosage is a 10-mg tablet once daily or a 70-mg tablet once weekly.

Prevention: Fosamax, the recommended dosage is a 5-mg tablet once daily or a 35-mg tablet once weekly.

Actonel has the same dosing requirements for both the treatment and prevention of osteoporosis, which is 1 oral 5-mg tablet daily or 35-mg tablet once weekly.

Selective Estrogen Receptor Modulattws (SERMs) are “designer” estrogens that demonstrate estrogen agonist effects on the skeletal and cardiovascular systems with estrogen antagonist effects on breast and uterine tissue.

They are referred to as SERMs because they have selective effects on estrogen target tissues.

They were developed to provide the benefits of estrogen therapy without the risks. There are new SERMs currently under development.

Evista® (raloxifene hydrochloride, Eli Lilly) is the first SERM approved for the prevention and treatment of osteoporosis.

Similar to estrogen, Evista decreases bone resorption and overall bone turnover as evidenced by decreases in levels of urine and serum biochemical markers of bone turnover.

The biologic activity of Evista is carried out through binding to estrogen receptor, which regulate gene expression.

Selective Estrogen Receptor ModulatorsSelective Estrogen Receptor Modulators

The Use of SERMs in the Treatment and Prevention of Osteoporosis

Available agents in United States

Raloxifene: (Evista, Eli Lilly)

Bone disease indications Prevention and treatment of postmentopausal osteoporosis

Effects A selective estrogen receptor mediator

Binds to estrogen receptors

Reduces resorption of bone

Decreases overall bone turnover

Safety Common adverse event considered to be drug related:

Hot flashes (menopausal side effects)

Leg cramps

Precautions about use in patients with a history of thromboembolic events.

Mode of administration Oral 60-mg tablet

Effects on BMD, fracture risk, and lipids

Clinical data from a 3-year, multicenter, randomized, double-blind trial Multiple Outcomes of Raloxifene Evaluation (MORE) indicate that raloxifene (Evista) increases BMD by about 2%.

Compared to estrogen, these increases are smaller.

However, the MORE study results also demonstrate that raloxifene reduces the risk of new vertebral fractures in patients with preex isting fractures by 30%.

Evista also has nonskeletal benefits similar to estrogen, demonstrating decreases in total cholesterol and LDL or “bad” cholesterol. However, unlike estrogen, Evista does not increase HDL or “good” cholesterol.

Effects on BMD, fracture risk, and lipids

Evista does not demonstrate estrogen-like effects on uterus and breast tissue.

Unlike estrogen, it is not effective in relieving vasomotor symptoms of menopause (hot flashes).


Hot flashes and leg cramps are common side effects of Evista treatment.

An increased risk of venous thromboembolic events is a serious side effect, with the greatest risk occurring during the first 4 months of treatment.

There has been no increased risk of breast or endonetrial cancer reported with Evista for up to 30 months in clinical trials.

Similar to estrogen, Evista is contraindicated in women with a history of venous thromboembolic events including pulmonary embolism, deep vein thrombosis, and retinal vein thrombosis.

Administration

The recommended dosage of Evista is 60 mg/day, taken orally, for the prevention and treatment of osteoporosis.

The dose may be taken at any time of the day, regardless of meals.

MIACALCIC Nasal Spray -Product Knowledge

MIACALCIC Nasal Spray has been approved for the treatment of osteoporosis in more than 70 countries and was launched in the United States in late 1995.

Description

MIACALCIC Nasal Spray is indicated for the treatment of postmenopausal osteoporosis in women who are more than 5 years postmenopause with low bone mass who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated.

Like the injectable formulation of MIACALCIC Nasal Spray contains a synthetic calcitonin similar to the calcitonin found in salmon.

Called salmon calcitonin or calcitonin-salmon, this synthetic polypeptide has 32 amino acids (the building blocks of proteins) lined up in the same sequence as in the calcitonin produced by salmon.

MIACALCIC Nasal Spray is an effective treatment for postmenopausal osteoporosis.

Clinical Pharmacology

The actions of calcitonin-salmon are essentially the same as those of human cakitonin, D but calcitonin-salmon is up to 40 times more potent and has a longer duration of action.

How calcitonin acts on bone and how it functions in the normal dynamics of human bone have yet to be fully understood.

Receptors for calcitonin have been discovered on the cell membranes of osteoclasts (cells that tear down bone) and osteoblasts (cells that rebuild bone).

With prolonged injectable calcitonin therapy, the number of osteoclasts in human bone decreases and the osteoclasts that remain appear to be less active.

Clinical Pharmacology

In vitro studies show that calcitonin-salmon inhibits osteoclast function with loss of the ruffled osteoclast border responsible for resorption of bone.

Some evidence also suggests that calcitonin may increase osteoblastic activity, helping to form new bone.

Postmenopausal osteoporosis

Based on more than 20 years of clinical trials in the United States and abroad, calcitonin salmon has been demonstrated to be an effective treatment for postmenopausal osteoporotic women.

Therapy with calcitonin-salmon has been shown to have positive effects on the bones most susceptible to fracture in this patient population, namely the vertebrae of the spinal column.

Bone biopsy studies of patients treated with MIACALCIC injectable indicate that it helps the body build normal bone.

Because the nasal spray formulation contains the same calcitonin-salmon as the injectable, it can be assumed that normal bone is produced with MIACALCIC Nasal Spray as well.

Postmenopausal osteoporosis

Several placebo-controlled, double-blind, randomized trials have shown that MIACALCIC Nasal Spray provides safe and effective treatment of postmenopausal osteoporosis.

For osteoporotic women who are more than 5 years postmenopause with low bone mass, MIACALCIC Nasal Spray 200 lU/day (one spray, once a day, anytime, anywhere): Stops bone loss and increases BMD

Calcium homeostasis

In 2 clinical studies of healthy volunteers, administration of MLACALCIC Nasal Spray (100 to 1600 IU) caused rapid and sustained small decreases in both total serum calcium (calcium in the blood) and serum ionized calcium, although values still remained within the normal range.

Hypocalcemia (abnormally low levels of calcium in the blood) has not been reported in any study of healthy volunteers or postmenopausal women.

Kidneys

Studies with injectable calcitonin-salmon show that it increases renal excretion of phosphate, calcium, and sodium by decreasing the resorption of these ions from renal tubules.

Gastrointestinal tract

Some studies with the injectable formulation demonstrate that calcitonin-salmon may have some effects on the GI tract.

Short-term injectable therapy reduces the volume and acidity of gastric juice, as well as the volume of the enzyme (trypsin and amylase) content of pancreatic juice.

Whether these effects persist with long-term injectable calcitonin therapy has not been studied.

MIACALCIC Nasal Spray bypasses the GI tract and, in clinical trials, demonstrated a much lower incidence of GI upset (2%) than the injectable formulation.

Pharmacokinetics and metabolism

MIACALCIC Nasal Spray is absorbed rapidly by the moist lining of the nose (the nasal mucosa).

Peak plasma levels occur 31 to 39 minutes after nasal administration (vs 16 to 25 minutes after injection).

In normal volunteers, about 3% of a nasally administered dose is bioavailable compared to the same dose administered by intramuscular injection (directly into the substance of the muscle).

The half-life of elimination is 43 minutes.

Repeated administration of MIACALCIC Nasal Spray at 10-hour intervals for up to 15 days does not result in accumulation of the drug.

This is an important difference from Fosamax, which has a half-life of approximately 10 years

Indication

MIACALCIC Nasal Spray is indicated for the treatment of established postmenopausal osteoporosis in women who:

1. Are more than 5 years postmenopause with low bone mass relative to healthy premenopausal women

2. Refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated

Co-administration of adequate calcium (1000-1500 mg/day) and vitamin D (400-600 lU/day) is recommended in conjunction with MLACALCIC Nasal Spray.

Summary of Efficacy Studies

Five double-blind, randomized, parallel, placebo-controlled studies involving 551 patients treated for 1 to 2 years served as the basis for the original FDA submission for MIACALCIC Nasal Spray and led to its approval in the treatment of postmenopausal osteoporosis.

Summary of Efficacy Studies These studies demonstrated:

1. Daily therapy with MIACALCIC Nasal Spray (200 LU, or one spray, once a day, anytime, anywhere) consistently increased BMD of lumbar vertebrae compared to baseline and placebo in osteoporotic women who were more than 5 years postmenopause; patients receiving 200 IU MIACALCLC Nasal Spray showed increased lumbar vertebral BMD of 1.4% versus baseline and 3.1% versus placebo at 24 months

2. Statistically’ significant increases in lumbar vertebral BMD occurred as early as 6 months after starting MLACALCIC Nasal Spray therapy

3. The overall improvement in lumbar vertebral BMD was 2% to 3% in patients treated daily with 200 IU of MIACALCIC Nasal Spray compared to patients who received calcium and nasal placebo over a 24-month period.

4. This gain of 2% to 3% in vertebral BMD is comparable to that seen in postmenopausal osteoporotic women treated with estrogen therapy for similar periods of time

Summary of Efficacy Studies

1. While not designed to detect differences in fracture rates, 1 study showed that the incidence of patients with new vertebral fractures was about two-thirds less in patients treated with MJACALCIC Nasal Spray than in patients treated with placebo.

2. This difference was statistically significant, however, given that these results were derived from pooled data across the 3 dosage groups studied (50 IU, 100 IU, and 200 IU), and that this methodology was not stated from the outset, this information was not permitted as part of our labeling

3. In 1 clinical study, a statistically significant increase in hip BMD was seen after 1 year of treatment, changing to a trend at 2 years that was no longer statistically significant

The PROOF Study: 5-year Results

The PROOF study is a 5-year multicenter, randomized, double-blind, placebo-controlled

1. Study conducted by Novartis.

2. This is the first large study designed to look specifically at vertebral fractures as a study end point.

3. A total of 1255 postmenopausal women with established osteoporosis were enrolled and randomized to receive placebo or 100 IU, 200 IU, or 400 IU of MIACALCIC Nasal Spray daily.

Study Design

*Intent-to treat patients are patients who take at least 1 study dose of medication and show an efficacy end *Intent-to treat patients are patients who take at least 1 study dose of medication and show an efficacy end point (i.e., 1 follow-up x-ray). Per protocol patients are patients who take the required amount of study point (i.e., 1 follow-up x-ray). Per protocol patients are patients who take the required amount of study medication to completion of the trial. Because 200 LU is the approved dosing for MIACALCIC Nasal Spray, medication to completion of the trial. Because 200 LU is the approved dosing for MIACALCIC Nasal Spray, this section will focus on the results demonstrated in the 200 IU group compared with the placebo group after this section will focus on the results demonstrated in the 200 IU group compared with the placebo group after 5 years of treatment.5 years of treatment.

Summary of Results

Significantly reduced the risk of new vertebral fractures by 33% in intent-to-treat patients*(P=.03)

Significantly reduced new vertebral fracture risk by 36% in per protocol patientst (P=.03)

A modest yet statistically significant 1.2% increase in lumbar spine BMD (LS-BMD) yielded a 33% reduction in the risk of fractures in the “intent-to-treat patients”

Additional Findings

Intent-to-treat patients* experienced a 35% reduction in the risk of multiple (2 or more) new vertebral fractures (P=.13)

Per protocol patient's experienced a 45% reduction in the risk of developing multiple (2 or more) new vertebral fractures (P=.06)

Although not statistically significant, a 48% reduction in hip fractures was observed in the 200 IU group (n=5/315) vs placebo (n=9/305) in the “intent-to-treat” population.

However, a larger study would be needed to adequately assess reduction of hip fracture

Additional Findings Not Statistically Significant

A subgroup analysis of patients over 75 years of age showed a 62% risk reduction (P=.03) in the number of new vertebral fractures with 200 IU of MIACALCIC Nasal Spray (12/58) relative to placebo (19/47)

At 3 Years 200 IU Salmon Calcitonin NS Reduces New Vertebral Fractures by 37%

0

5

10

15

20

25

Pat

ien

ts w

i th

P

ati e

nts

wi t

h >>

1 n

ew

1

ne

w

v ert

ebra

l fr

actu

r e (

%)

vert

ebra

l fr

act u

r e (

%)

PlaceboPlacebo 200 IU salmon calcitonin 200 IU salmon calcitonin NSNS

37% 37%

p=0.037p=0.037

Stock et al., JBMR 1997, 12(1)Stock et al., JBMR 1997, 12(1)

At 5 Years 200 IU Salmon Calcitonin NS Reduces New Vertebral Fractures by 36% in Women With 1-5 Prevalent Vertebral Fractures at Baseline

0

10

20

30

40

50

60

70

Pat

i en

ts w

ith

P

atie

nt s

wit

h >>

1 n

e w v

erte

bra

l 1

ne w

ver

teb

ral

frac

tur e

(%

)fr

act u

r e (

%)


36% 36%

p=0.03p=0.03

Chesnut et al., AJM 2000, Vol 109, 267-276Chesnut et al., AJM 2000, Vol 109, 267-276

At 5 Years 200 IU Salmon Calcitonin NS Reduces New Vertebral Fractures by 33%

0

5

10

15

20

25

30

All

Pat

ien

ts (

%)

All

Pat

ien

ts (

%)

PlaceboPlacebo 200 IU salmon calcitonin NS200 IU salmon calcitonin NS

33% 33%

p=0.03p=0.03

Chesnut et al., AJM 2000, Vol 109, 267-276Chesnut et al., AJM 2000, Vol 109, 267-276

200 IU Salmon Calcitonin NS is Effective Across All Age Groups

A post-hoc stratification of the PROOF data was carried out to test the hypothesis that salmon calcitonin NS would be a particularly effective and safe therapy to prevent vertebral fractures in women above 70 years of age

Vertebral fracture reduction was calculated using odds ratio analysis

At 5 Years 200 IU Salmon Calcitonin NS Reduces New Vertebral Fractures by 53% in Women >70 Years

0

5

10

15

20

25

30

35

40

Wo

men

>70

yea

rs w

ith

W

om

en >

70 y

ears

wi t

h >>

1 n

e w v

erte

bra

l 1

new

ver

teb

ral

frac

ture

(%

)fr

act u

re (

%)


53% 53%

p=0.012p=0.012

Silverman et al., Third Amsterdam menopause symposium abstract book 2001, page 91Silverman et al., Third Amsterdam menopause symposium abstract book 2001, page 91

At 5 Years 200 IU Salmon Calcitonin NS Reduces New Vertebral Fractures by 62% in Women >75 Years

0

5

10

15

20

25

30

35

40

45

Wo

men

>75

yea

rs w

ith

W

om

en >

75 y

ears

wit

h >>

1 n

ew

1 n

ew

vert

ebra

l fra

ctu

re (

%)

vert

ebra

l fra

ctu

re (

%)

PlaceboPlacebo 200 IU salmon 200 IU salmon calcitonin NScalcitonin NS

62% p=0.02862% p=0.028

Silverman et al., JBMR 2001, 16(1), S530Silverman et al., JBMR 2001, 16(1), S530

200 IU Salmon Calcitonin NS is Effective Across All Age Groups 1,2

05

10

15

20

25

30

35

45

40

36%*

53%*62%*

CalcitoninCalcitoninPlaceboPlacebo Primary analysisPrimary analysis

Patients with 1-5Patients with 1-5Vertebral fracturesVertebral fractures

Post-hoc analysisPost-hoc analysis

All patients All patients >> 70 70 All patients > 75All patients > 75

*p<0,05

Pati

en

ts (

%)

wit

h v

ert

eb

ral fr

actu

res

Pati

en

ts (

%)

wit

h v

ert

eb

ral fr

actu

res

1. Chesnut et al., AJM 2000, Vol 109, 267-276. 2. Silverman et al., JBMR 2001, 1. Chesnut et al., AJM 2000, Vol 109, 267-276. 2. Silverman et al., JBMR 2001, 16(1), S53016(1), S530

Effect of Salmon Calcitonin NS* on Hip Fracture at 3 Years

0

0.5

1

1.5

2

2.5

PlaceboPlacebo Salmon calcitonin NS*Salmon calcitonin NS*

Pat

ien

ts w

i th

hi p

fra

c tu

re (

%)

Pa t

i en

ts w

i th

hip

fra

ctu

re (

%)

72% P=0.04672% P=0.046

Silverman et al., Third Amsterdam menopause symposium abstract book Silverman et al., Third Amsterdam menopause symposium abstract book 2001, page 912001, page 91

*combined 100 IU and 200 IU doses

Effect of Salmon Calcitonin NS* on Hip Fracture at 5 Years

0

0.5

1

1.5

2

2.5

3

3.5

PlaceboPlacebo Salmon calcitonin Salmon calcitonin NS*NS*

Pat

ien

ts w

i th

hi p

fra

c tu

re (

%)

Pa t

i en

ts w

i th

hip

fra

ctu

re (

%)

68% p=0.04768% p=0.047

Silverman et al., Third Amsterdam menopause symposium abstract book 2001, page 91Silverman et al., Third Amsterdam menopause symposium abstract book 2001, page 91

*combined 100 IU and 200 IU doses*combined 100 IU and 200 IU doses

Conclusion

These data: 1. support the use of Miacalcic® 200 IU daily in reducing

the risk of vertebral fractures in postmenopausal and elderly osteoporotic women

2. show that Miacalcic® 200 IU daily may have a benefit in reducing the relative risk of hip fractures in postmenopausal osteoporotic women

CH. Chesnut et al, ASBMR 2001, PosterCH. Chesnut et al, ASBMR 2001, Poster

Safety Result

MIACALCIC Nasal Spray was well tolerated, with mild to moderate rhinitis as the only drug-related significant adverse event

Discontinuation Rates

Approximately 40% of the patients completed all 5 years of the study (about a 12% dropout rate per year)

Patients withdrew from the study primarily because of illness unrelated to taking MIACALCIC Nasal Spray and withdrawal of consent

The Concept of Bone Quantity vs Bone Quality

Increases in BMD were thought to directly correlate with decreases in fracture reduction.

Physicians have commonly accepted that increases in BMD are the best gauge of fracture reduction risk.

However, small increases in BMD may produce significant reductions in fracture risk that are comparable to those produced by larger increases in BMD.

So something other than BMD (bone quantity) seems to be affecting fracture risk.

To answer this question, key thought leaders theorize that factors other than increases in BMD may affect bone strength and the risk of fractures.

These factors include architecture, mineralization, organic matrix, and damage state, which are measurements of bone quality.


These factors include architecture, mineralization, organic matrix, and damage state, which are measurements of bone quality.

Since BMD measurements cannot assess bone quality, increases in BMD may not be a suitable predictor of fracture reduction and the efficacy of antiresorptive drugs.

If BMD is used as the sole gauge of efficacy, MIACALCIC Nasal Spray may appear less effective.

But in fact, the use of calcitonin results in less bone loss during the bone turnover process, thereby maintaining or even improving the functional quality of bone.


Currently the concept of “bone quality” is put to test with QUEST (Qualitative Effects of Salmon-Calcitonin Therapy).

QUEST is a double-blind, placebo-controlled, 2-year study designed to evaluate the effects of MIACALCIC Nasal Spray on bone quality, bone mineral density, and bone turnover in postmenopausal women with 1 to 5 new vertebral fractures.

Analgesic Benefits

The analgesic (pain-relieving) properties of MIACALCIC Nasal Spray have been shown in several studies.

In 1 clinical study, 18 patients with pain due to vertebral fractures were treated with either 200 IU per day of MIACALCIC Nasal Spray or nasal placebo.

Patients included in this controlled, double-blind pilot study had 1 to 4 spinal fractures.

At the first patient visit after treatment had begun, both analgesic use and pain were decreased compared to baseline in patients treated with MIACALCIC Nasal Spray.

At weeks 3 and 4, the reduction in analgesic consumption and pain was significant among the MIACALCIC Nasal Spray group compared with the placebo group.

Contraindications and warnings

The only contraindication for MIACALCIC Nasal Spray is clinical allergy to the active ingredient calcitonin-salmon.

Because calcitonin-salmon is a protein, there is the possibility that a systemic allergic reaction could occur in response to this agent

More than 13.4 million prescriptions have been written for MIACALCIC Nasal Spray since its launch in late 1995.

Only a few cases of systemic allergic reactions attributable to the nasal spray formulation have been reported.

If it is suspected that a patient might have sensitivity to calcitonin, skin testing with a small amount of injectable calcitonin-salmon should be considered before starting MIACALCIC Nasal Spray therapy.

Precautions

No formal studies have been done to evaluate whether drug interactions occur with calcitonin-salmon.

No such interactions have been observed to date.

A comprehensive literature search revealed no reported drug interactions with MIACALCIC Nasal Spray.

In fact, unlike other therapies such as Fosamax, MIACALCIC Nasal Spray can be safely administered with oral medications without compromising absorption or efficacy of the drug.

Periodic visual exams of the nasal linings and cavities, including the nasal mucosa, turbinates, septum, and mucosal blood vessel status, are recommended.

Precautions

If a patient develops severe ulcers in the nasal mucosa (eg, larger than 1.5 mm in diameter or penetrating below the mucosa) or heavy bleeding, treatment with MIACALCIC Nasal Spray should be discontinued.

Smaller ulcers often heal without interrupting MIACALCIC Nasal Spray therapy, although it is recommended that the medication be temporarily discontinued until healing occurs.

There are no adequate and well-controlled studies of calcitonin-salmon therapy in children or pregnant women.

Adverse Reactions

Compared to injectable calcitonin-salmon, MIACALCIC Nasal Spray has fewer troublesome adverse effects.

For example, MIACALCIC Nasal Spray therapy is associated with a lower incidence of nausea (1.8% vs 10%) and flushing (1% vs 2% to 5%) than injectable calcitonin-salmon.

In the pivotal trials discussed in the current package insert, the overall incidence of adverse reactions with MIACALCIC Nasal Spray’ was low and not much greater than that seen with placebo.

Most adverse reactions were mild to moderate in severity. Nasal adverse events were most common, with 70% mild, 25% moderate, and 5% severe in nature (vs placebo rates of 71 % mild, 27% moderate, and 2% severe).

MIACALCIC Nasal Spray

Placebo

N= 341 N= 341

Adverse reaction % of Patients % of Patients

Rhinitis 12.0 6.9

Symptom of nose* 10.6 16.0

Back pain 5.0 2.3

Arthralgia 3.8 5.3

Epistaxis 3.5 4.6

Headache 3.2 4.6

*Symptom of nose includes: nasal crusts, dryness, redness or erythema, nasal sores, irritation, itching, thick feeling, soreness, pallor, infection, stenosis, runny/blocked, small wound, bleeding wound, tenderness, uncomfortable feeling, and sore across bridge of nose.

Dosage and Administration

The recommended daily dose of MIACALCIC Nasal Spray for postmenopausal osteoporotic women is 200 IU administered intranasally; alternating nostrils daily.

In simpler terms, this means one spray; once a day, anytime, anywhere, in alternate nostrils.

Before the first dose, the pump must be primed.

The bottle should be held upright and the 2 white side arms depressed toward the bottle until a full spray is emitted.

The pump is activated once this first full spray has been emitted.

At this point, the nozzle should be placed into the nostril with the head in an upright position, and the pump depressed toward the bottle.


The patient should not reactivate the pump before each daily dose, as this will waste the medication.

Patients treated with MIACALCIC Nasal Spray should ensure adequate intake of both calcium and vitamin D.

According to the National Institutes of Health (NIH), premenopausal women and postmenopausal women on estrogen therapy should take 1000 mg of calcium daily.

Postmenopausal women who are not taking estrogen therapy should take 1500 mg of calcium daily.

The recommended dosage of vitamin D is 600 to 800 LU daily.

How MIACALCIC NS Is Supplied

MIACALCIC Nasal Spray is supplied as a metered-dose solution in 2 mL glass bottles containing 2200 IU of calcitonin-salmon per milliliter.

The dosage strength is 200 IU (0.09 ml) per spray.

The dose is delivered by activation of the screw-on pump provided with each glass bottle.

Each glass bottle provides 2 weeks or 14 daily doses of therapy.

This nasal spray formulation of calcitonin-salmon is convenient and easy to use, which is important to ensure continued compliance in the targeted patient population.

How MIACALCIC NS Is Supplied

The unopened bottle should be refrigerated at 36T to ~ (2~C to 8~C) and protected from freezing.

After a pump has been activated, the solution is stable at room temperature and should be maintained at room temperature until the medication has been completed (a period of 2 weeks).

MIACALCIC Nasal Spray is safe and well tolerated.

MIACALCIC Nasal Spray vs Injectable

MIACALCIC Nasal Spray MIACALCIC Injection

Indication Treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause with

low bone mass who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated

Treatment of postmenopausal osteoporosis, symptomatic

Paget’s disease of bone, and hypercalcemia.

Biovailability 3% compared to injectable

Adverse reactions Local effects (eg, rhinitis and other symptoms of the nose)

Systemic effects (eg, flushing,

nausea).


200 IU per day, administered

Instranasally

100IU (SC or IM) every other day (for postmenopausal

osteoporosis).

How supplied Metered-dose solution in 2ml

bottles, Delivers 200 IU per spray

2-ml vials containing 200 IU per mL

Leading Products to Manage Postmenopausal Osteoporosis

Prevention

Treatment

Prevention of postmenopausal osteoporosis

Estrogen is the mainstay therapy for the prevention of osteoporosis.

Studies have shown the benefit of ERT and HRT in slowing or halting postmenopausal bone loss.

Data from a 2-year prospective study demonstrated that women receiving estrogen and calcium had a 2.3% mean increase from baseline in spinal BMD.

Conversely, women receiving calcium supplements alone or no treatment at all had a decrease from baseline in spinal BMD of 10.5% (P=.0001) and 9.0% (P=.002), respectively.


To achieve optimum preventive benefit with ERT, it is advised that women begin therapy within 5 years of menopause and continue therapy indefinitely because some studies have found that upon discontinuation, bone loss recurs.

Evista, a SERM, is indicated for the prevention and treatment of postmenopausal osteoporosis.

The results of a 3-year, multicenter, randomized, double-blind, placebo-controlled study demonstrated a modest increase in spinal BMD of approximately 2% with the use of Evista compared with placebo (P<.00 1); results for hip and total body BMD were similar.

Fosamax has also been shown to prevent postmenopausal bone loss.

Results from a 3-year, multicenter, double-blind, placebo-controlled trial demonstrated that at 36 months, patients receiving Fosamax 5 mg had a mean increase in spinal BMD of approximately 3% to 4%; in contrast, patients receiving placebo lost approximately 3% to 4% of BMD at the spine. R

Results for other sites (ie, hip) were similar for the Fosamax- and placebo-treated groups.

A 5-mg once-daily or a 35-mg once-weekly dose of alendronate is approved for the prevention of osteoporosis.


Actonel, a bisphosphonate, has also been shown to prevent bone loss in postmenopausal women.

Results from a 2-year double-blind placebo-controlled study of women within 3 years of menopause (age range 42 to 63 years) indicate that 5 mg of risedronate daily produced significant mean increases in BMD at the lumbar spine, femoral neck, and trochanter compared with placebo.


Treatment of postmenopausal osteoporosis

MIACALCIC Nasal Spray (calcitonin-salmon) is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated.

Ellerington and colleagues (1996), demonstrated a mean increase in spinal BMD of 1.4% vs baseline, in addition to a mean increase in spinal BMD of 3.1% vs placebo.

In another clinical trial, Overgaard (1992), demonstrated a mean increase in spinal BMD of approximately 3% vs baseline.

Although not designed primarily to detect differences in fracture rates, this study demonstrated a reduction in the rate of new vertebral fractures of approximately two thirds when data from all MJACALCIC Nasal Spray treatment groups were pooled.

Results of the 5-year PROOF study, which evaluated 1255 postmenopausal osteoporotic women with 1 to 5 preexisting vertebral fractures at baseline, confirmed the results of this study by demonstrating a significant reduction in the risk of new vertebral fractures (36%).


Although not statistically significant, the PROOF study also showed a 48% reduction in the risk of hip fractures; 1.6% (5/315) of patients in the 200-lU group vs 3.0% (9/305) of patients in the placebo group experienced a hip fracture.

This study suggests a protective effect of MIACALCIC Nasal Spray on hip fractures. However, the study was not designed to detect differences in hip fracture rates, and a much larger patient population is required to quantif~,i such differences.


Fosamax (alendronate) is indicated for the treatment of osteoporosis in postmenopausal women, which may be confirmed by detection of low bone mass or by the presence or history of osteoporotic fracture.

Fosamax therapy has been shown to increase BMD of the hip and spine as well as reduce the risk of fracture.

A multicenter study including 881 women followed for 3 years assessed the effect of Fosamax on the risk of vertebral fractures.

Subjects were 45 to 80 years of age and at least 5 years postmenopause at entry. The results of this study demon strated a 48% reduction in the risk of new vertebral fractures in women treated with Fosamax.

Similarly, the first arm of the multicenter FIT study, assessing the impact of Fosamax on fracture reduction, showed a 47% reduction in the risk of new vertebral fractures.


This arm of the study followed more than 2000 osteoporotic women 2 or more years postmenopause with low BMD at the hip and at least 1 vertebral fracture.

In addition, results showed a reduction in the risk of hip fractures of approximately 50%.

A second arm of the FIT examined more than 4400 women with low BMD and no preexisting fracture.

Results of this arm showed a similar reduction in the risk of fracture.

It also demonstrated that treatment with alendronate offered no fracture reduction benefit for women whose BMD was from 2.0 to 2.5 SD below the average of young healthy women.

A 10-mg once-daily or a 70-mg once-weekly dose of alendronate is approved for the treatment of osteoporosis.


Actone1 (risedronate) is indicated for the treatment of osteoporosis in postmenopausal women.

The fracture efficacy of Actonel 5 mg daily in the treatment of osteoporosis was determined in 2 large, randomized, placebo-controlled studies that enrolled approximately 4000 postmenopausal women with established osteoporosis.

The multinational study (VERT MN) was primarily conducted in Europe and Australia, and the North American study (VERT NA) was conducted in the United States and Canada.

The primary end point for these studies was to determine the incidence of new and worsening vertebral fractures over a period of 0 to 3 years.

Within 1 year of treatment, risedronate demonstrated a 65% reduction in the risk of new vertebral fractures compared with placebo (2.4% risedronate-treated patients vs 6.4% placebo-treated patients, a 4% reduction in absolute risk).


However, after 3 years of treatment, the relative risk of fracture was reduced by 41%.

Risedronate also showed a statistically significant increase in BMD at the spine, hip, and wrist compared with placebo.

The efficacy of Actonel for preventing hip fractures was recently evaluated by the Hip Intervention Program (HIP) Study Group.

Participants in this randomized, placebo controlled study included women between 70 and 79 years old who had osteoporosis and women at least 80 years old who had at least 1 non-skeletal risk factor for hip fracture or a low BMD at the femoral neck.

Participants received either 2.5 mg or 5 mg risedronate, or placebo.

Approximately 4600 women completed 3 years of treatment Risedronate significantly reduced the risk of hip fracture by approximately 30% for women between 70 and 79 who participated in the study.


Evista (raloxifene) is also indicated for the treatment of postmenopausal osteoporosis.

The MORE study was a double-blind, placebo-controlled, clinical trial to evaluate the effect of Evista on the risk of vertebral fractures in 7705 women with osteoporosis.

The results of the 3-year analysis in women with previous fractures demonstrated a reduction in the risk of new vertebral fractures of 30.6%


Patients with no previous fractures were about half as likely to experience a new spinal fracture.

In addition, this study has shown no difference in the proportion of women reporting hip fractures (nontraumatic, nonspine fractures) among those receiving Evista (8.5%) and those receiving placebo (9.3%).

Miacalcic NS vs Fosamax

MIACALCIC Nasal Spray can be used anytime, anywhere, offering reliable absorption and efficacy for typical postmenopausal osteoporosis patients (eg, those with age-related issues).

Because of its safety profile and complicated dosing restrictions, Fosarnax may not be ideal for patients who have gastrointestinal (GI), esophageal, or renal disorders, who take multiple medications, who have set daily routines, who have difficulty remaining upright, or who have mental disabilities that preclude them from following the dosing instructions without supervision.

Product MIACALCIC Nasal Spray Fosamax Tablets

Generic name Calcitonin-salmon Alendronate sodium

Manufacturer Novartis Merck

Indications Treatment of postmenopausal osteoporosis in women more than 5 years postmenopause with low Bone mass who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated

Prevention of osteoporosis in post-menopausal women (5-mg dose daily or a 35-mg dose once weekly); treatment of osteoporosis in postmenopausal women (10-mg daily dose or a 70-mg once-weekly dose); treatment of Paget’s disease of bone in men and women (40-mg dose); treatment and prevention of corti - costeroid-induced osteoporosis in men and women (5-mg dose); and treatment to increase bone mass in men (10-mg dose)

Efficacy Stops bone loss; helps build bone mass

Stops bone loss; helps build bone mass; reduces risk of fractures (vertebral, hip, wrist)

Miacalcic NS vs Fosamax tabsMiacalcic NS vs Fosamax tabs

Product MIACALCIC Nasal Spray Fosamax Tablets

Safety/side effects

Well tolerated

Side effects include rhinitis (12.0% vs 6.9% with placebo) and other nasal symptoms (10.6% vs 16.0% with placebo)

Rare potential for systemic allergic reaction

Side effects include abdominal pain (6.6% vs 4.8% with placebo) and bone, muscle, or joint pain (4.1% vs 2.5% with placebo)

Safety concerns include esophagitis, esophageal erosions, esophageal ulcers, oropharyngeal ulceration, and gastric or duodenal ulcers

Dosing 200 IU admisntered intranasally; one spray, once a day in alternate nostrils

Adequate calcium and vitamin D intake recommended

5 - or 10-mg tablet once per day

35-mg tablet once daily

40-mg tablet once daily (paget’s disease)

70-mg tablet once a week

Must be taken at least 30 minutes bedore first food, drink, or medication of the day

Must be taken with a 6-8 oz glass of plain water only

After taking emdication, patient must remain upright for 30 mintues and until after her first food of the day

Adequate calcium and vitamin D intake recommende

Risedronate (Actonel) is a bisphosphonate and has the same strict dosing requirements as alendronate (Fosamax), which may adversely affect patient compliance.

Unlike alendronate, risedronate demonstrates a promising safety profile.

These results reflect outcomes that are achieved within a well-controlled clinical setting.

There’s another point to remember about the safety of bisphosphonates.

MIACALCIC Nasal Spray & Actonel

The use of Fosamax and Actonel results in long-term integration of bisphosphonates in the bone, with a half-life exceeding 10 years.

The consequences of this long-term retention of Fosamax and Actonel are unknown.

The safety of calcitonin-salmon has been established over a longer period of time than alendronate and risedronate.

Calcitonin-salmon has been used for 20 years worldwide; the first reported use of alendronate was in the early 1990s while the first reported use of risedronate was in the late 1990s.

MIACALCIC Nasal Spray & Actonel

Product MIACALCIC Nasal Spray Actonel Tablets

Generic name calcitonin-salmon risedronate sodium

Manufacturer Novartis Procter & Gamble, Aventis (co-marketeis)

Indications Treatment of postmenopausal osteoporosis in women more that 5 years postmenopause with low bone mass who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated.

Prevention and treatment of osteoporosis in postmenopausal women (5-mg dose); gluccocorticoid-induced osteoporosis in postmenopausal women (5-mg dose); treatment of Paget’s disease of bone (30-mg dose)

Efficacy Stops bone loss; helps build bone mass

Stops bone loss; helps build bone mass; reduces risk of fractures (vertebral and wrist)

Product MIACALCIC Nasal Spray Actonel Tablets

Safety/side effects Well toleratedSide effects include trinities (12.0% vs. 6.9% with placebo and other nasal symptoms (10.6% vs. 16.0% with placebo)Rare potential for systemic allergic reaction

Side effects include back pain (26.1% vs. 23.6% with placebo), bone, muscle, or joint pain (23.7% vs. 21.1% with placebo), and abdominal pain (11.6% vs. 9.4% with placebo)Safety concerns include dysphagia and esophageal or gastric ulcers.

Dosing 200 IU administered intranasally; one spray, once a day, in alternate nostrilsAdequate calcium and vitamin D intake recommended

5 – or 30-mg tablets once per week Must be taken at least 30 minutes before first food, drink, or medication of the day Must be taken with a 6 to 8 oz glass of plain water only After taking medication, patient must remain upright for 30 minutes and until after her first food of the day Adequate calcium and vitamin D intake recommended

MIACALCIC NasaL Spray and Evista

Raloxifene has shifted its original position as a “designer estrogen” that provides the benefits of HRT without the risk of breast and endometrial cancer to a treatment and prevention therapy for osteoporosis with “proven protection and tolerability.”

This position is similar to our message of effective therapy that is convenient, well tolerated, and allows patients to lead an independent lifestyle

Raloxifene’s protection message doesn’t ring true for many patients who find it difficult to tolerate menopausal symptoms such as hot flashes and leg cramps.

Also, it can’t protect patients who may be at risk of thromboembolic events—particularly those who are inactive or live in an LTC facility.

MIACALCIC NasaL Spray and Evista

With more than 20 years of documented safety, MIACALCIC Nasal Spray proves to be the appropriate choice for physicians who are looking for an effective, well-tolerated treatment option for women with postmenopausal osteoporosis.

Comparison of MIACALCIC Nasal Spray and Evista

Product MIACALCIC Nasal Spray Evista Tablets

Generic name calcitonin-salmon raloxifene hydrochloride

Manufacturer Novartis Eli Lilly

Indications Treatment of postmenopausal osteoporosis in women more than 5 years postmenopause with low bone mass who refuse or cannot tolerate estrogens, or in whom estrogens are contraindicated

Prevention and treatment of osteoporosis in postmenopausal women (60-mg dose)

Efficacy Stops bone loss; helps build bone mass Stops bone loss; helps build bone mass; reduces risk of fractures (vertebral, ankle)

Safety/side effects Well toleratedSide effects include rhinitis (12.0% vs 6.9% with placebo) and other nasal symptoms (10.6% vs 16.0% with placebo) Rare potential for systemic allergic reaction

Safely concerns include prolonged restrictive movement due to increased risk of thromboembolic events (3.1 times higher in raloxifene group vs placebo group)

Dosing 200 IU administered intranasally; one spray, once a day, in alternate nostrilsAdequate calcium and vitamin D intake recommended

60-mg tablet once per dayMust move about periodically during prolonged immobilityAdequate calcium and vitamin D intake recommended

Market Analysis

Materials

Master DA DC DC Note pad Patient leaflet, how to use MIA Patient leaflet, osteoporosis awareness Quick screen QUEST reprints Pen

Activities

ME workshop, SharmAVAsRTD

Treget specialties

RheumOrthEndoIMNeurosurgObs/Gyn

Thank you

miacalcic training 2004 platform syr april 03

Health & Medicine